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Cancer: Diagnosis by extracellular vesicles
•Clotilde Théry
The detection of a single molecule anchored to circulating extracellular vesicles allows late-stage pancreatic
cancer to be identified from just one drop of a patient's blood. See Article p.177
Nature. 2015 Jul 9;523(7559):177-82. doi: 10.1038/nature14581. Epub 2015 Jun 24.
Glypican-1 identifies cancer exosomes and detects early pancreatic cancer.
Melo SA1, Luecke LB1, Kahlert C1, Fernandez AF2, Gammon ST3, Kaye J1, LeBleu VS1, Mittendorf
EA4, Weitz J5, Rahbari N5, Reissfelder C5, Pilarsky C5,Fraga MF6, Piwnica-Worms D3, Kalluri R1.
Author information
Abstract
Exosomes are lipid-bilayer-enclosed extracellular vesicles that contain proteins and nucleic acids.
They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancercell-derived exosomes in the circulation is currently lacking. Using mass spectrometry analyses, we
identify a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer-cellderived exosomes. GPC1(+) circulating exosomes(crExos) were monitored and isolated using flow
cytometry from the serum of patients and mice with cancer. GPC1(+) crExos were detected in the
serum of patients with pancreatic cancer with absolute specificity and sensitivity, distinguishing
healthy subjects and patients with a benignpancreatic disease from patients with early- and latestage pancreatic cancer. Levels of GPC1(+) crExos correlate with tumour burden and the survival
of pre- and post-surgical patients. GPC1(+) crExos from patients and from mice with
spontaneous pancreatic tumours carry specific KRAS mutations, and reliably
detect pancreatic intraepithelial lesions in mice despite negative signals by magnetic resonance
imaging. GPC1(+) crExos may serve as a potential non-invasive diagnostic and screening tool to
detect early stages of pancreatic cancer to facilitate possible curative surgical therapy.
Myeloid disease: Another action of a thalidomide derivative
•Takumi Ito & Hiroshi Handa
Lenalidomide effectively treats a blood disorder caused by the 5q chromosomal deletion. A study shows that
the drug binds to its target, CRBN, to promote the breakdown of an enzyme encoded by a gene in the 5q
region. See Article p.183
Nature. 2015 Jul 9;523(7559):183-8. doi: 10.1038/nature14610. Epub 2015 Jul 1.
Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS.
Krönke J1, Fink EC2, Hollenbach PW3, MacBeth KJ3, Hurst SN4, Udeshi ND5, Chamberlain
PP3, Mani DR5, Man HW3, Gandhi AK3, Svinkina T5, Schneider RK4, McConkey M4, Järås
M4, Griffiths E6, Wetzler M6, Bullinger L7, Cathers BE3, Carr SA5, Chopra R3, Ebert BL2.
Abstract
Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion
of
chromosome
5q
(del(5q)).
Here,
we
demonstrate
that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin
ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)), resulting in CK1α degradation.
CK1α is encoded by a gene within the common deleted region for del(5q) MDS and
haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic
basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells
are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the
corresponding human residue enables lenalidomide-dependent degradation of CK1α. We
further demonstrate that minor side chain modifications in thalidomide and a novel analogue,
CC-122, can modulate the spectrum of substrates targeted by CRL4(CRBN). These findings
have implications for the clinical activity oflenalidomide and related compounds, and
demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.
Scientific Reports